Keratitis, Ulceration, and Perforation
`Associated with Topical Nonsteroidal
`Anti-inflammatory Drugs
`
`Ann C. Guidera, MD,1,2 Jodi I. Luchs, MD,1,2 Ira J. Udell, MD1,2
`
`Purpose: To report corneal complications associated with topical nonsteroidal anti-inflammatory drugs
`(NSAIDs).
`Design: Retrospective, noncomparative interventional case series.
`Participants: Eighteen eyes of 16 patients with adverse corneal events associated with NSAID use.
`Methods: Evaluation of 16 patients referred for management of corneal complications during use of topical
`NSAIDs (ketorolac tromethamine [Acular], diclofenac sodium [Voltaren], diclofenac sodium [Falcon DSOS]).
`Main Outcome Measures: Type and severity of corneal complications.
`Results: Of the 16 patients, two experienced severe keratopathy, three experienced ulceration, six experi-
`enced corneal or scleral melts, and five experienced perforations. Eleven patients had recent cataract surgery;
`nine of these were on concurrent topical steroids and antibiotics. Another patient who did not have recent surgery
`was using concurrent topical steroids without antibiotics for sarcoid uveitis. Systemic associations included two
`patients with rheumatoid arthritis, one patient with asymptomatic Sjogren’s syndrome, and two with rosacea.
`Conclusions: Topical NSAIDs were associated with corneal complications in 18 eyes of 16 patients.
`Potential risk factors include conditions that predispose the patient to corneal melting, concurrent topical
`steroids, and epithelial keratopathy in the early postoperative period. Ophthalmology 2001;108:936 –944 © 2001
`by the American Academy of Ophthalmology.
`
`Nonsteroidal anti-inflammatory drugs (NSAIDs) are cyclo-
`oxygenase inhibitors with well-established anti-inflamma-
`tory, analgesic, and antipyretic effects. Topical formulations
`of NSAIDs for ophthalmic use became commercially avail-
`able worldwide by the early 1990s. Currently, their multiple
`and varied uses in ophthalmology include the inhibition of
`intraoperative miosis, management of postoperative inflam-
`mation, treatment of ocular allergic conditions, and, more
`recently, the control of pain after photorefractive keratec-
`tomy (PRK) and other excimer laser procedures. Nonsteroi-
`dal anti-inflammatory drugs are also widely used for the
`prevention and treatment of postoperative cystoid macular
`edema (CME) despite the lack of definitive proof of efficacy
`and without US Food and Drug Administration approval for
`these indications. There have been multiple reports that
`NSAIDs decrease the incidence of postoperative angio-
`graphic CME,1– 6 as well as improve visual acuity.7–9
`Topical NSAIDs are often considered a safer alternative
`
`to topical corticosteroids, avoiding the potential undesirable
`side effects associated with topical steroids, such as eleva-
`tions in intraocular pressure (IOP), progression of cataracts,
`increased risk of infection, and worsening of stromal melt-
`ing. It is well known that topical corticosteroids can sup-
`press the repair process and potentiate corneal ulceration.
`Although topical NSAIDs have been associated with de-
`layed epithelial healing, to our knowledge there is only one
`recent report published subsequent to our submitting this
`paper of corneal ulceration with melting and perforation
`associated with topical NSAID use.10
`We describe 16 patients (18 eyes) with corneal compli-
`cations suspected to be related to the use of topical NSAIDs.
`Two patients had severe surface toxicity at presentation; the
`other 14 experienced frank ulcerations. Of these 14, perfo-
`rations developed rapidly in five (one bilateral) and six
`experienced corneoscleral or corneal stromal thinning (one
`bilateral).
`
`Originally received: December 13, 1999.
`Manuscript no. 99820.
`Accepted: September 11, 2000.
`1Department of Ophthalmology, Long Island Jewish Medical Center, New
`Hyde Park, New York.
`2Long Island Campus, Albert Einstein College of Medicine, New Hyde
`Park, New York.
`Presented in part as a poster at the American Academy of Ophthalmology
`annual meeting, Orlando, Florida, October 1999.
`Reprint requests to Ann C. Guidera, MD, Department of Ophthalmology,
`Long Island Jewish Medical Center, 600 Northern Boulevard, Suite 214,
`Great Neck, NY 11021.
`
`936
`
`© 2001 by the American Academy of Ophthalmology
`Published by Elsevier Science Inc
`
`Patients and Methods
`
`Sixteen patients referred for corneal complications while using
`topical NSAIDs were studied. For each patient, a clinical history
`was evaluated for concurrent topical medications and preexisting
`ocular or systemic conditions. When possible, blood tests were
`performed to screen for autoimmune processes that may predis-
`pose patients to corneal complications. Every attempt was made to
`verify the accuracy of the patients histories, which were primarily
`obtained from the patient or referring physician.
`
`ISSN 0161-6420/00/$–see front matter
`PII S0161-6420(00)00538-8
`
`SENJU EXHIBIT 2079
`LUPIN v SENJU
`IPR2015-01105
`
`PAGE 1 OF 9
`
`

`
`Guidera et al
`
`z Corneal Complications Associated with Topical NSAIDs
`
`Table 1. Patient Data
`
`Patient
`No.
`
`Age
`(Range,
`43–90
`yrs)
`
`52
`90
`83
`76
`72
`77
`86
`82
`70
`43
`67
`88
`43
`62
`79
`80
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`
`Results
`
`Gender
`(M:F,
`7:9)
`
`Male
`Female
`Male
`Female
`Female
`Male
`Male
`Female
`Female
`Male
`Female
`Female
`Male
`Female
`Female
`Male
`
`Eye
`(Right: Left:
`Bilateral, 8:6:2)
`
`Right
`Left
`Right
`Right
`Right
`Right
`Right
`Right
`Left
`Right and left
`Left
`Left
`Left
`Right and left
`Right
`Left
`
`The 16 patients ranged in age from 43 to 90 years. There were
`seven men and nine women. Eight cases involved the right eye, six
`
`the left eye, and two were bilateral (Table 1). The findings in the
`sixteen patients are summarized in Tables 2, 3, and 4.
`Severe keratitis developed in two patients (Table 2). One pa-
`tient had been using ketorolac for 16 days, and the other initially
`used preserved, then preservative-free, ketorolac for 5 to 6 weeks.
`Both patients 1 and 2 had slow but complete resolution of their
`keratitis over several months with return to their baseline vision.
`Ulceration of the conjunctiva or cornea without tissue loss
`developed in three patients (Table 2). These ulcerations were noted
`in the area of cataract incisions, all within 2 weeks of surgery. All
`three ulceration patients were receiving diclofenac (diclofenac
`sodium ophthalmic solution [DSOS]; Alcon, Fort Worth, Texas)
`with concurrent topical steroids and antibiotics. In two of these
`three, patients 3 and 4, the ulcerations healed within 10 days of
`discontinuing diclofenac with excellent postoperative visual acu-
`ities of 20/25 and 20/20. Patient 5 moved out of state and was lost
`to follow-up.
`Corneal or scleral melts developed in six patients (Table 3).
`Five were at the site of clear corneal or scleral tunnel cataract
`incisions. These five were using diclofenac (DSOS) with concur-
`rent topical steroids and antibiotics. One of these five had used
`diclofenac (DSOS) before surgery as well. One of the six patients
`(Patient 10, with sarcoid) had not had recent cataract surgery and
`experienced bilateral central corneal melting on diclofenac
`(Voltaren, CIBA Vision, Duluth, Georgia), while using glaucoma
`medications as well as steroids. In each of these patients, the
`
`Table 2. Keratitis and Ulceration (without Loss of Tissue)
`
`Patient
`No.
`
`1
`
`Corneal
`Complication
`
`Keratitis, right eye,
`(stromal and
`epithelial)
`
`Nonsteroidal
`Anti-inflammatory
`Drug Regimen
`
`Ketorolac
`four times daily
`for CME, then
`nonpreserved
`ketorolac self-dosed
`every 2 hrs
`
`Type of
`Cataract
`Surgery
`
`Nonsteroidal
`Anti-inflammatory
`Drug Use
`(Initiation)
`Duration
`
`Other
`Medications
`at Time of
`Presentation
`
`Treatment
`Regimen
`
`Scleral
`tunnel
`
`(6 wks p/o)
`5 wks
`
`None
`
`Tears every 2 hrs
`ofloxacin twice daily
`
`Associated
`Conditions
`
`CME
`
`2
`
`Keratitis, left eye
`
`Ketorolac
`four times daily
`
`Temporal clear
`cornea; right eye
`7 yrs earlier
`
`(POD 12)
`16 days
`
`None
`
`Topical twice daily
`steroids, nonpreserved
`tears
`
`Glaucoma
`(large bleb),
`dry eyes
`
`3
`
`4
`
`5
`
`Ulceration,
`right eye,
`of conjunctiva
`over incision
`
`Diclofenac
`(DSOS)
`four times daily
`
`Scleral tunnel
`
`(POD 1)
`13 days
`
`Prednisolone,
`ciprofloxacin
`
`Tobramycin,
`dexamethasone
`
`Anemia
`ASCVD
`
`Ulceration, right eye,
`and infiltrate at
`limbus and peripheral
`cornea
`
`Conjunctival
`abscess, ulcer,
`right eye, with
`infiltrate; culture neg
`
`Diclofenac (DSOS)
`four times daily
`
`Temporal scleral
`tunnel
`
`(POD 1)
`6 days
`
`Prednisolone,
`ciprofloxacin
`
`Tobramycin,
`dexamethasone
`
`Diclofenac
`(DSOS)
`four times daily
`
`Clear cornea;
`OS 3 wks earlier, same
`meds, no problems
`
`(POD 1)
`11 days
`
`Prednisolone,
`ciprofloxacin
`
`Neomycin,
`polymyxin B,
`gramacidin,
`ciprofloxacin, bacitracin;
`then fort antibotics,
`prednisolone, bacitracin
`
`None
`
`None
`
`ASCVD 5 atherosclerotic cardiovascular disease; CME 5 cystoid macular edema; DSOS 5 diclofenac sodium ophthalmic solution (Alcon Pharmaceu-
`ticals); OS 5 left eye; POD 5 postoperative day.
`
`937
`
`PAGE 2 OF 9
`
`

`
`Ophthalmology Volume 108, Number 5, May 2001
`
`Table 3. Corneal and Scleral Melts
`
`Patient
`No.
`
`Corneal
`Complication
`
`Nonsteroidal
`Anti-inflammatory
`Drug Regimen
`
`Type of
`Cataract Surgery
`
`Diclofenac
`(DSOS)
`four times daily
`
`Temporal
`scleral
`tunnel
`
`Nonsteroidal
`Anti-inflammatory
`Drug Use
`(Initiation)
`Duration
`
`Other
`Medications
`at Time of
`Presentation
`
`(POD 2)
`10 days
`
`Rimexolone,
`ciprofloxacin
`
`Associated
`Conditions/
`Rheumatoid Status
`(If Known)
`
`Treatment
`Regimen
`
`Discontinue
`diclofenac,
`more ciprofloxacin,
`less rimexolone
`
`ABM
`dystrophy
`
`6 Melt, right eye,
`of sclera with
`conjunctival
`defect; culture
`negative
`
`7 Melt, right eye,
`at cataract wound
`and ulceration at
`sideport; culture
`negative
`
`Diclofenac
`(DSOS)
`four times daily
`
`Temporal
`clear cornea
`
`(POD 1)
`18 days
`
`Prednisolone,
`ciprofloxacin
`
`BSCL,
`topical
`antibiotics
`
`Rosacea, NIDDM,
`heart disease,
`2ANA, 2RF,
`2Sjo¨gren’s Ab
`
`8 Melt at scleral
`tunnel noted at
`vitrectomy;
`culture negative
`
`Diclofenac
`(DSOS)
`four times daily
`
`Scleral tunnel,
`retained
`nucleus
`
`(POD 1)
`1 mo
`
`Prednisolone,
`ciprofloxacin,
`timolol,
`dorzolamide,
`cyclogyl
`
`Discontinue
`diclofenac
`
`Glaucoma
`
`9 Melt, left eye,
`at cataract wound
`
`Diclofenac
`(DSOS)
`four times daily
`
`10 Central melt,
`right eye
`Central melt,
`left eye
`
`Diclofenac
`(Voltaren)
`Diclofenac
`(Voltaren)
`
`11 Ulceration, melt,
`left eye, and
`infiltration;
`culture negative
`
`Diclofenac
`(DSOS)
`twice daily
`
`Temporal
`clear cornea;
`right eye 15 mos
`earlier with
`CME treated
`with diclofenac,6
`no problems
`
`(POD 1)
`3.5 mos
`(ulceration
`first noted
`at day 6)
`
`N/A
`
`19 days
`
`Neomycin,
`polymyxin B,
`dexamethasone
`
`Discontinue
`diclofenac
`
`IDDM, RA
`
`Fluoromethalone,
`betaxolol,
`hyoscine
`
`Glue/BSCL,
`topical
`antibiotics,
`lubricating
`ointment
`
`Sarcoid uveitis, scar,
`SPK, IDDM
`
`Temporal
`clear cornea;
`right eye 1/99,
`no nonsteroidal
`anti-inflammatory drugs,
`no problems
`
`(2 mos after
`surgery)
`3 wks
`
`Tobramycin,
`tears
`
`Topical
`antibiotics
`
`None
`
`ABM 5 anterior basement membrane; ANA 5 antinuclear antibodies; BSCL 5 bandage soft contact lens; CME 5 cystoid macular edema; DSOS 5
`diclofenac sodium ophthalmic solution (Alcon); IDDM 5 insulin-dependent diabetes mellitus; N/A 5 not applicable; NIDDM 5 non–insulin-dependent
`diabetes mellitus; POD 5 postoperative day; RA 5 rheumatoid arthritis; RF 5 rheumatoid factor; SPK 5 superficial punctate keratopathy.
`
`epithelium healed 2 weeks to several months after stopping di-
`clofenac, with stable thinning of 50% to 80% of stromal thickness.
`Patient 6 achieved a visual acuity of 20/25. Patient 7 healed with
`50% thinning and a visual acuity of 20/30 with his native cylinder.
`Patient 8 was lost to follow-up. Patient 9 healed with 80% thinning
`and a visual acuity of 20/30, with significantly increased cylinder.
`Patient 10 experienced central corneal scarring and thinning with
`visual acuities of 20/100 and counting fingers. Patient 11 had
`corneal decompensation with a visual acuity of counting fingers.
`Perforations developed in five patients (Table 4). One was at
`the site of a scleral tunnel cataract incision. This patient had been
`
`topical steroids, antibiotics, and
`receiving diclofenac (DSOS),
`glaucoma medications, and required a pericardial patch graft. One
`month after surgery, visual acuity was 20/50. Four patients expe-
`rienced central perforations requiring corneal transplant surgery.
`Two were using ketorolac and one was using preservative-free
`ketorolac. None of these four central corneal perforation patients
`had been taking concurrent steroids. All have clear grafts with
`postoperative visions of roughly 20/70.
`Representative case reports of patients with keratitis, ulceration
`with melt, and scleral and corneal perforations are presented. All
`cases are presented in the tables.
`
`938
`
`PAGE 3 OF 9
`
`

`
`Guidera et al
`
`z Corneal Complications Associated with Topical NSAIDs
`
`Table 4. Corneal and Scleral Perforations
`
`Patient
`No.
`
`12
`
`Corneal
`Complication
`
`Perforation,
`left eye, at
`scleral tunnel;
`culture negative
`
`Nonsteroidal
`Anti-inflammatory
`Drug Regimen
`
`Type of
`Cataract
`Surgery
`
`Diclofenac
`(DSOS)
`four times daily
`
`Scleral tunnel;
`other eye,
`no nonsteroidal
`anti-inflammatory
`drugs, no problems
`
`Nonsteroidal
`Anti-inflammatory
`Drug Use (Initiation)
`Duration
`
`Other
`Medications
`at Time of
`Presentation
`
`Associated
`Conditions/
`Rheumatic Status
`(If Known)
`
`Treatment
`Regimen
`
`(POD 2)
`18 days
`
`Prednisolone,
`tobramycin,
`atropine,
`timolol,
`latanaprost
`
`Patch graft Atrial
`fibrillation/1RA
`
`13
`
`14
`
`Central
`perforation
`
`Ketorolac
`as required
`
`Central perforation,
`left and right eyes;
`culture negative
`
`Nonpreserved
`ketorolac
`
`N/A
`
`N/A
`
`3 wks
`
`None
`
`PK
`
`Rosacea/weakly
`1ANA, 2RF
`2Sjo¨gren’s AB
`
`4 days
`
`None
`
`PK both eyes Previously
`undiagnosed
`Sjo¨gren’s,
`1ANA, 1RF
`
`15
`
`Central perforation,
`right eye
`
`Ketorolac
`as required
`
`N/A
`
`1 mo
`
`Tears as required
`
`PK
`
`Old scar,
`epithelial
`downgrowth/
`weakly 1ANA,
`2RF, 2Sjo¨gren’s AB
`
`16
`
`Corneal
`perforation,
`left eye
`
`Diclofenac
`(Voltaren),
`then diclofenac
`(DSOS)
`twice daily
`
`N/A
`
`10 mos
`
`5 mos
`
`Ofloxacin
`each hr
`
`PK
`
`CME6, 2ANA, 2RF
`
`ANA 5 antinuclear antibodies; CME 5 cystoid macular edema; DSOS 5 diclofenac sodium ophthalmic solution (Alcon); N/A 5 not applicable; PK
`5 penetrating keratoplasty; POD 5 postoperative day; RA 5 rheumatoid arthritis; RF 5 rheumatoid factor.
`
`Case Reports
`
`Patient 1
`
`A 52-year-old male underwent uncomplicated phacoemulsification
`cataract surgery with posterior chamber lens implantation in the
`right eye. Postoperative best-corrected visual acuity was 20/15. Six
`weeks later, his vision in the right eye decreased to 20/100 –2 as a
`result of angiographically proven CME. He was treated with
`ketorolac and prednisolone acetate (Pred Forte, Allergan, Irvine,
`CA), both four times daily. The vision improved to 20/20 –1 over
`the next 3 weeks, at which time he was instructed to taper off both
`drops.
`After 5 weeks of topical NSAID use, he sought treatment for
`cloudy vision that he had been experiencing for 2 weeks. Central,
`disciform-like stromal edema with mild microcystic edema was
`present, and the acuity was decreased to 20/60 –3. He was still
`taking prednisolone acetate and ketorolac once daily, which he was
`instructed to stop, and started sodium chloride (Muro 128, Bausch
`& Lomb, Tampa) 2% solution four times daily in the right eye.
`However, he continued to take ketorolac, up to every 2 hours,
`partially for pain relief (Figs 1 and 2).
`One week later, he sought treatment for extreme pain in the
`right eye with increasingly blurry vision over 2 weeks. Medica-
`mentosa was suspected as a result of ketorolac toxicity. Ketorolac
`was discontinued. A pressure patch was placed the following day
`because of pain from the punctate epithelial keratitis surrounding
`
`the central plaquelike epithelial lesion. Descemet’s striae were
`present.
`Three days later, the cornea was slightly clearer surrounding
`the central plaque. Ultrasound pachymetry (Sonogage, Chiron,
`Ophthalmics) was 0.621 in the right eye and 0.540 in the left eye.
`He was treated with ofloxacin (Ocuflox) and prednisolone acetate
`twice daily, and he improved slowly.
`
`Patient 7
`An 86-year-old man with non–insulin-dependent diabetes mellitus
`and a history of atherosclerotic heart disease underwent uneventful
`cataract surgery in the right eye by phacoemulsification through a
`temporal clear corneal incision under peribulbar anesthesia. On the
`first postoperative day, the patient had an elevated IOP and was
`placed on betaxolol (Betoptic, Alcon, Fort Worth, TX) and bri-
`monidine (Alphagan, Allergan, Irvine, CA) in addition to pred-
`nisolone four times daily, ciprofloxacin (Ciloxan, Alcon, Fort
`Worth, TX) four times daily, and diclofenac (DSOS) four times
`daily. He had also been pretreated with diclofenac (DSOS) four
`times daily for 1 day before surgery. Three days after surgery, his
`IOP was well controlled, and both betaxolol and brimonidine were
`discontinued. At a routine postoperative visit 2.5 weeks after
`surgery, the patient was asymptomatic, but was found to have
`ulcerations with corneal thinning at the sites of the cataract wound
`and sideport incision. The patient was referred to Long Island
`Jewish Medical Center Cornea Service.
`
`939
`
`PAGE 4 OF 9
`
`

`
`Ophthalmology Volume 108, Number 5, May 2001
`
`Figure 1. Patient 1. The photograph shows severe stromal and epithelial
`keratitis.
`
`Figure 3. Patient 7. The photograph shows corneal ulceration and melt at
`clear corneal cataract and SidePort incisions.
`
`On examination, the patient’s visual acuity was counting fin-
`gers at 3 feet, pinholing to 20/80 in the right eye and 20/50 in the
`left eye. Slit-lamp examination of the right eye revealed diffuse
`superficial punctate keratopathy and localized corneal ulceration at
`both the temporal cataract wound (50% thinned) and the 12-
`o’clock SidePort incision (Figs 3 and 4). There was a moderate
`anterior chamber reaction. He was noted to have facial features
`suggestive of rosacea.
`Cultures were sent that later showed no growth. The diclofenac
`(DSOS) was discontinued and topical steroids were tapered. Top-
`ical antibiotics were increased to one drop every 2 hours while
`awake. One week later, the patient had persistent epithelial defects
`with stable stromal thinning at the temporal clear corneal cataract
`incision. A bandage soft contact lens was placed for several weeks,
`topical antibiotics were tapered, and doxycycline 50 mg orally
`twice daily was added. The epithelium healed very slowly over 1
`month, with stable thinning. Four months after surgery, the patient
`was correctable to 20/30 in the right eye with his native cylinder.
`
`Patient 12
`An 88-year-old woman with a history of rheumatoid arthritis and
`atrial fibrillation underwent uneventful cataract surgery of the left
`eye by phacoemulsification through a scleral tunnel incision. She
`had an elevated IOP with significant inflammation on her first
`postoperative day and was treated with timolol (Timoptic, Merck,
`West Point, PA) and latanoprost (Xalatan, Pharmacia & Upjohn,
`
`Peapack, NJ) in addition to prednisolone acetate 1% every 2 hours,
`tobramycin four times daily, and diclofenac (DSOS) four times
`daily. One week after surgery, her IOP was controlled and the
`timolol, the latanoprost, and the tobramycin were discontinued.
`Three weeks after surgery, she was noted to have anterior lamellar
`melting of the scleral tunnel incision. Pred Forte was discontinued,
`and diclofenac was increased to every 3 hours. Ofloxacin every
`hour was added. Over 2 days, melting progressed to become Seidel
`positive with pressure, and the patient was referred to LIJ (Fig 5).
`Cultures were taken which later revealed no growth. The di-
`clofenac (DSOS) was discontinued. Fortified cefazolin and forti-
`fied tobramycin were started every hour while awake in place of
`the ofloxacin. Oral ciprofloxacin 250 mg orally bid was added.
`Because of persistent leak and progressive hypotony despite med-
`ical therapy and a trial of a bandage soft contact lens, a patch graft
`of pericardial tissue was performed over the site of the thinning
`scleral tunnel incision and adjacent limbal area. One month later,
`the patient was improved with a visual acuity of 20/50 (Fig 6).
`Of note, the patient had undergone cataract surgery in the right
`eye 1 year earlier, was treated after surgery with topical steroids
`but not topical NSAIDs, and had an uneventful postoperative
`course.
`
`Patient 14
`A 62-year-old woman with a history of dry eyes, suspected glau-
`coma, and cataracts experienced irritation of both eyes. Her med-
`
`Figure 2. Patient 1. The photograph shows fluorescein staining.
`
`Figure 4. Patient 7. The photograph shows fluorescein staining.
`
`940
`
`PAGE 5 OF 9
`
`

`
`Guidera et al
`
`z Corneal Complications Associated with Topical NSAIDs
`
`Figure 5. Patient 12. The photograph shows scleral melt and perforation
`at scleral tunnel cataract incision.
`
`Figure 8. Patient 14. The photograph shows central descemetocele in the
`left eye.
`
`Figure 6. Patient 12. The photograph shows a pericardial patch graft.
`
`Figure 7. Patient 14. The photograph shows central corneal ulceration
`and melt with 50% stromal thinning in the right eye.
`
`Figure 9. Patient 14. The photograph shows a slit-beam view of descem-
`etocele in the left eye.
`
`ications included preservative-free tears and timolol 0.25%. She
`was found to have punctate staining of both corneas. She was
`treated with trimethoprim/polymyxin B (Polytrim, Allergan, Ir-
`vine, CA) and fluorometholone for 10 days. Two weeks after
`treatment was completed, the patient had persistent punctate stain-
`ing and was prescribed preservative-free ketorolac drops alone
`four times daily in both eyes. After four days of ketorolac therapy,
`the patient noted decreased vision and was found to have central
`corneal ulceration and thinning in both eyes. She experienced a
`descemetocele in the left eye and was referred to LIJ.
`At presentation, the patient did not report any pain but had
`pseudomembranous conjunctivitis. Both the right and left corneas
`had central ulceration with no stromal infiltrate. The right cornea
`was 50% thinned centrally, and the left cornea had a central
`descemetocele. There was no anterior chamber reaction in either
`eye (Figs 7, 8, and 9).
`Corneal cultures were examined (no growth in the right eye,
`Staphylococcus aureus sensitive to aminoglycosides in the left
`eye), and topical fortified cefazolin and tobramycin drops were
`prescribed every hour in both eyes. The descemetocele of the left
`cornea had become weakly Seidel positive. Three days later, the
`left cornea experienced perforation with a flat anterior chamber.
`Cyanoacrylate glue was applied, and a contact lens was placed
`with deepening of the anterior chamber.
`
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`
`Ophthalmology Volume 108, Number 5, May 2001
`
`A penetrating keratoplasty of the left eye with tarsorrhaphy of
`both eyes was performed. A conjunctival biopsy revealed acute
`inflammatory cells. Despite the addition of topical cyclosporine
`1% six times daily in the right eye, oral prednisone 60 mg once
`daily, and oral doxycycline 50 mg twice daily, the right cornea
`showed progressive thinning. Three days after corneal transplant
`of the left eye, a corneal transplant was performed for a descem-
`etocele of the right eye. At 5 months after surgery, the patient had
`a visual acuity of 20/70 in the right eye and 20/100 pinholing to
`20/70 in the left eye with clear grafts in both eyes.
`Although there were no reported symptoms suggestive of an
`arthritic, collagen vascular or autoimmune disorders, rheumato-
`logic evaluation revealed significant seroreactivity, including a
`positive antinuclear antibodies (.1280, speckled and spindle pat-
`tern), high rheumatoid factor (120), an erythrocyte sedimentation
`rate of 20 on oral prednisone, and a normal angiotensin converting
`enzyme level. The patient’s erythrocyte sedimentation rate later
`rose to 100 off oral steroids. The patient was believed to have
`asymptomatic Sjogren’s syndrome.
`
`Discussion
`
`Nonsteroidal anti-inflammatory drugs are an important class
`of anti-inflammatory agents with a wide variety of thera-
`peutic applications throughout medicine. The most com-
`monly described side effects of topical NSAIDs are local
`burning, stinging, and conjunctival hyperemia.11 Patients
`may also experience allergic or hypersensitivity reactions
`with some cross-reactivity with aspirin. Other adverse
`events have been described such as corneal epithelial tox-
`icity, delayed epithelial healing, acute subepithelial infiltra-
`tive keratitis after photorefractive keratectomy,12 a rare case
`of acute exacerbation of asthma,13 and acceleration of cor-
`neal ulceration in an experimental model of Pseudomonas
`keratitis.14
`We described 16 patients (18 eyes) who experienced
`corneal problems after the initiation of topical NSAIDs
`(range, 4 days to 15 months). In an effort to try to identify
`patients at risk for these complications, we asked the fol-
`lowing questions.
`Are there associated systemic or ocular conditions that
`place patients at risk for these complications? Several of
`these patients had underlying systemic or ocular conditions
`that can be associated with corneal melting. Two patients
`had known rheumatoid arthritis (one experienced corneal
`melting, and one experienced scleral perforation), one pa-
`tient had previously undiagnosed Sjo¨gren’s syndrome (and
`experienced bilateral corneal perforations), and two patients
`had rosacea (one experienced corneal melt, and one expe-
`rienced corneal perforation). Four of the other patients un-
`derwent blood work and were found to have very low or
`negative antinuclear antibodies, negative rheumatoid factor,
`and negative Sjo¨gren’s antibodies.
`Although each of these conditions has been associated
`with corneal melting and perforation, the precipitous onset
`of rapid corneal melting was temporally associated with the
`start of NSAID use. This suggests that these agents may act
`as a trigger for the onset of melting in a cornea predisposed
`to melting. Other systemic diseases occurring in these pa-
`tients include diabetes, anemia, and sarcoidosis. Concurrent
`
`942
`
`ocular conditions include glaucoma, uveitis, and anterior
`basement membrane dystrophy.
`Cultures were obtained in six patients, one of whose
`cultures grew S. aureus that was believed to be a contami-
`nant.
`What specific NSAID was used? Nine patients were using
`diclofenac (DSOS), one patient was using diclofenac
`(Voltaren), one patient used both diclofenac (DSOS) and
`diclofenac (Voltaren), three patients were using ketorolac,
`one patient used preservative-free ketorolac, and one patient
`used both preserved and nonpreserved ketorolac. Four of
`these patients (patients 2, 10, 13, and 14) had been using
`topical NSAIDs before diclofenac (DSOS) was available.
`Were concurrent topical medications used? Nine pa-
`tients were using topical steroids and antibiotics concurrent
`with the topical NSAID. One patient was using steroid
`drops without antibiotics. One patient was using antibiotics
`without steroids. Three patients were using glaucoma med-
`ications. One patient was using lubricating tears, and four
`patients were not using any concurrent eyedrops.
`The preservatives and vehicles of these medications and
`of the NSAIDs may also contribute to epithelial toxicity. Of
`note, two patients (one with severe keratitis and one with
`corneal perforation) were using preservative-free ketorolac
`alone at the time of their corneal complication.
`How was the NSAID dosed and what was the time course
`to development of corneal complication? The frequency of
`topical NSAID use ranged from twice daily to every 2 hours
`while awake. In 15 of the 16 cases, corneal or scleral
`problems were identified shortly after the initiation of
`NSAID use (range, 4 days–3.5 months). In patient 16, the
`patient had been treated with diclofenac (Voltaren) for 10
`months before substitution of diclofenac (DSOS), which
`was used twice daily for an additional 5 months before
`corneal ulceration and perforation occurred. Because many
`patients were asymptomatic, we are only able to report
`when corneal complications were identified, which may
`have been later than the actual onset of these events.
`Did the patient have recent eye surgery? When were
`NSAIDs given and what complications developed? An im-
`portant subset of these patients is the 11 patients treated
`with topical nonsteroidal drugs within 3 months of cataract
`surgery.
`Eight of the eleven patients began using NSAIDs in the
`early postoperative period (all were given diclofenac on the
`first or second postoperative day). Three of these eight were
`found to have ulcerations at their cataract wound after 6, 11,
`and 13 days using NSAIDs. Four of the eight patients
`experienced corneal or scleral melts after 10 days, 18 days,
`1 month, and 3.5 months of NSAID use. One of these four
`patients also used topical NSAIDs before surgery four times
`daily for 3 days. One experienced a scleral perforation after
`18 days of NSAID use, requiring a patch graft.
`Three of the eleven patients began using NSAIDs in the
`mid to late postoperative period (one was given diclofenac
`[DSOS] and two were given ketorolac, preserved and non-
`preserved, 12 days to 2 months after surgery). Two patients
`experienced keratitis, one after 16 days and the other after 5
`weeks of ketorolac use. One experienced a corneal melt
`after 3 weeks of diclofenac (DSOS) use.
`
`PAGE 7 OF 9
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`
`Guidera et al
`
`z Corneal Complications Associated with Topical NSAIDs
`
`The time course in these cases suggests a causative role
`of the NSAIDs in the occurrence of corneal complications
`during the postoperative period. However, the concurrent
`use of other topical medications, particularly steroids, is a
`confounding factor. In addition, in many cases, the actual
`onset of corneal complication is unknown and may not
`correspond exactly with the first date that the complication
`was noted, because many of these patients were asymptom-
`atic and diagnosed at routine postoperative visits.
`Ten patients had uncomplicated cataract surgery. One
`was referred to a retina specialist for a retained nuclear
`fragment and was noted at the time of vitrectomy to have
`stromal melting at the scleral tunnel cataract incision. The
`other patients were essentially asymptomatic and were di-
`agnosed during routine follow-up examinations. Two pa-
`tients had pressure elevations on the first postoperative day.
`One was treated with betaxolol (Betoptic) and brimonidine
`for 2 days, the other with timolol and latanoprost for 1
`week.
`Had these patients had cataract surgery in the other eye,
`and were there similar complications? Five patients had
`previously undergone cataract surgery in the other eye with-
`out corneal complications. Four did not receive NSAIDs,
`and one had no adverse events with the same postoperative
`medical regimen of diclofenac, topical steroids, and antibi-
`otics. The use of NSAIDs both before and after surgery has
`been described as prophylaxis for CME in cataract surgery
`patients [McColgin AZ, Raizman MB. Invest Ophthalmol
`Vis Sci 1999;40(4):S289].
`Given our observations in this subset of patients, we
`strongly advise caution when using NSAIDs in the imme-
`diate postoperative period. It appears that there is a vulner-
`able period when there is a break in the epithelium which
`may facilitate ulceration, melting, or even perforation, par-
`ticularly in susceptible individuals. This appears to be true
`in both surgical and nonsurgical patients, such as patient 14,
`who had punctate staining, and a positive rheumatologic
`work up, and who experienced bilateral descemetoceles
`after 4 days of ketorolac use. Anecdotal reports of ulcer-
`ations in peripheral limbal relaxing incisions performed at
`the time of cataract surgery suggest an increased potential
`for corneal melts in nonshelved incisions with wound gap-
`ing.
`Nonsteroidal anti-inflammatory drugs exert their phar-
`macologic activity primarily by inhibiting cyclooxygenase,
`an enzyme in the metabolic pathway for the conversion of
`arachidonic acid to prostaglandins. Blockade of the cyclo-
`oxygenase arm of the arachidonic acid metabolic pathway
`by NSAIDs reduces the production of prostaglandins and
`mediators of inflammation. Arachidonic acid is also metab-
`olized via a second pathway catalyzed by lipoxygenase,
`resulting in the production of leukotrienes, lipoxins, and
`hydroperoxyeicosatetraenoic acids. A third P450-dependent
`pathway has also been described.
`It has been hypothesized that the selective blockade of
`cyclooxygenase by topical NSAIDs may allow unused ara-
`chidonic acid to be shunted into the lipoxygenase metabolic
`pathway.14,15 The resulting accumulation of hydroperoxyei-
`cosatetraenoic acids and leukotrienes provide potent che-
`moattractants for neutrophils, as well as vasoconstrictors
`
`and mediators of increased vascular permeability. In the
`cornea, these agents may enhance the ability of neutrophils
`to infiltrate. The accumulation of these agents through this
`mechanism has been hyp